Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent cancer worldwide with over 500,000 new cases diagnosed yearly1. While most HNSCC cases are associated with exposure to tobacco and alcohol or infection with the human papilloma virus (HPV), the majority of persons exposed do not develop cancer, suggesting genetic variation plays a role in susceptibility. A potential modifier of risk of progression to cancer in those exposed is the immune status of the host as determined by variability of immune-related genes2. Genetically engineered mice have provided evidence for cancer immunosurveillance in solid tumor models5. Immunodeficient mice have shown an increased frequency of tumor development compared to wild-type mice4,5. Likewise, immunosuppressed patients also have an increased risk for developing SCC. HPV-induced Oropharyngeal Cancer (OPC) appears intimately related to variants in immune- related genes because HPV infection is necessary but not sufficient for carcinogenisis7,8. Thus, HNSCC is an ideal model system for the analysis of immune genes modulating susceptibility to solid tumors. Typically, studies investigating the genetic determinants of risk of HNSCC examine only several single nucleotide polymorphisms (SNPs) and focus on variants in carcinogen metabolism and DNA repair genes12-15. Limitations in these studies include low statistical power in detecting modest risk sequence variants, false positive results, positive publication bias, and a moderate prior probability that each SNP individually confers substantial increase in risk14. To overcome these issues we will apply a novel strategy of analysis to the Genome Wide Association Study (GWAS) performed by the International Head and Neck Cancer Epidemiology Consortium using a hypothesis-driven multi-candidate gene approach and integrating improved methods for data quality control , candidate gene ranking and pathway analysis. We propose that genetic variations in host immune-related genes are associated with altered susceptibility to HNSCC. The aims of this proposal are: 1) Explore the association between genetic variations in immune-related genes and susceptibility to HNSCC and identify candidate immune-related genes associated with increased risk of developing HNSCC. Using data from the GWAS, we will evaluate the association between variants in the candidate genes and risk of HNSCC and perform a pathway based SNP association analysis to uncover complex immunogenetic associations to the risk of HNSCC. We will also perform a separate SNP association analysis of patients with HPV-induced OPC using a modified candidate immune-related genes list including genes related to both cancer and viral susceptibility and host response. 2) Validate highly ranked immune-related genes in an independent cohort of HNSCC cases and controls by performing replication studies using PCR analysis of genomic DNA.